After asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischemic or hypoxic insults to the central nervous system (CNS) of man a certain degree of damage in several different cell types may result. For example periventricular leucomalacia, a lesion which affects the periventricular oligodendrocytes is generally considered to be a consequence of hypoxicischemic injury to the developing preterm brain (Bejar et al., Am. J. Obstet. Gynecol., 159:357-363 (1988); Sinha et al., Arch. Dis. Child., 65:1017-1020 (1990); Young et al., Ann. Neurol., 12:445-448 (1982)). Further cholinergic neuronal cell bodies are absent from most regions of the cortex in primates (Mesulam et al., Neurosci., 12:669-686 (1984)) and rats (Brownstein et al. in Handbook of Chemical Neuroanatomy, Classical Transmitters in the CNS, Bjorklund et al., eds., Elsevier, Amsterdam, pp. 23-53 (1984)). Damage to the cerebral cortex by trauma, asphyxia, ischemia, toxins or infection is frequent and may cause sensory, motor or cognitive deficits. Glial cells which are non-neuronal cells in the CNS are necessary, for normal CNS function. Infarcts are a principle component of hypoxicischemic induced injury and loss of glial cells is an essential component of infarction.
Diseases of the CNS also may cause loss of specific populations of cells. For example multiple sclerosis is associated with loss of myelin and oligodendrocytes, similarly Parkinson's disease is associated with loss of dopaminergic neurons. Some situations in which CNS injury or disease can lead to predominant loss of glia or other non-cholinergic cell types or infarction include: perinatal asphyxia associated with fetal distress such as following abruption, cord occlusion or associated with intrauterine growth retardation; perinatal asphyxia associated with failure of adequate resuscitation or respiration; severe CNS insults associated with near miss drowning, near miss cot death, carbon monoxide inhalation, ammonia or other gaseous intoxication, cardiac arrest, collapse, coma, meningitis, hypoglycaemia and status epilepticus; episodes of cerebral asphyxia associated with coronary bypass surgery; cerebral anoxia or ischemia associated with stroke, hypotensive episodes and hypertensive crises; cerebral trauma.
There are many other instances in which CNS injury or disease can cause damage to glia and non-cholinergic neurons of the CNS. It is desirable to treat the injury in these instances. Also, it is desirable to prevent or reduce the amount of CNS damage which may be suffered as a result of induced cerebral asphyxia in situations such as cardiac bypass surgery. To date, there has been no reference in the prior art to the manipulation of insulin-like growth factor 1 (IGF-1) to prevent or treat CNS injury or disease leading to infarction or loss of glia and other non-cholinergic neuronal cells in vivo.
IGF-I is a polypeptide naturally occurring in human body fluids, for example, blood and human cerebral spinal fluid. Most tissues, and especially the liver, produce IGF-I together with specific IGF-binding proteins. IGF-I production is under the dominant stimulatory influence of growth hormone (GH), and some of the IGF-I binding proteins are also increased by GH. See Tanner et al., Acta Endocrinol., 84: 681-696 (1977); Uthne et al., J. Clin. Endocrinol. Metab., 39: 548-554 (1974)). IGF-I has been isolated from human serum and produced recombinantly. See, e.g., EP 123,228 and 128,733.
Various biological activities of IGF-I have been identified. For example, IGF-I is reported to lower blood glucose levels in humans. Guler et al., N. Engl. J. Med., 317: 137-140 (1987). Additionally, IGF-I promotes growth in several metabolic conditions characterized by low IGF-I levels, such as hypophysectomized rats [Skottner et al., J. Endocr., 112: 123-132 (1987)], diabetic rats [Scheiwiller et al., Nature, 323: 169-171 (1986)], and dwarf rats [Skottner et al., Endocrinology, 124: 2519-2526 (1989)]. The kidney weight of hypophysectomized rats increases substantially upon prolonged infusions of IGF-I subcutaneously. Guler et al., Proceedings of the 1st European Congress of Endocrinology, 103: abstract 12-390 (Copenhagen, 1987). The kidneys of Snell dwarf mice and dwarf rats behaved similarly, van Buul-Offers et al., Pediatr. Res., 20: 825-827 (1986); Skottner et al., Endocrinology, supra. An additional use for IGF-I is to improve glomerular filtration and renal plasma flow. Guler et al., Proc. Natl. Acad. Sci. USA, 86: 2868-2872 (1989). The anabolic effect of IGF-I in rapidly growing neonatal rats was demonstrated in vivo. Philipps et al., Pediatric Res., 23: 298 (1988). In underfed, stressed, ill, or diseased animals, IGF-I levels are well known to be depressed.
IGF-1 is thought to play a paracrine role in the developing and mature brain (Werther et al., Mol. Endocrinol., 4:773-778 (1990)). In vitro studies indicate that IGF-1 is a potent non-selective trophic agent for several types of neurons in the CNS (Knusel et al., J. Neurosci., 10(2):558-570 (1990); Svezic and Schubert, Biochem. Biophys. Res. Commun., 172(1):54-60 (1990)), including dopaminergic neurons (Knusel et al., J. Neurosci., 10(2):558-570 (1990)) and oligodendrocytes (McMorris and Dubois, J. Neurosci. Res., 21:199-209 (1988); McMorris et al., PNAS, USA, 83:822-826 (1986); Mozell and McMorris, J. Neurosci. Res., 30:382-390 (1991)). Methods for enhancing the survival of cholinergic neuronal cells by administration of IGF-1 have been described (Lewis, et al., U.S. Pat. No. 5,093,317 (issued Mar. 3, 1992)).
IGF-1 receptors are wide spread in the CNS (Bohannon et al., Brain Res., 444:205-213 (1988); Bondy et al., Neurosci., 46:909-923 (1992)) occurring on both glia (Kiess et al., Endocrinol., 124:1727-1736 (1989)) and neurons (Sturm et al., Endocrinol., 124:388-396 (1989)). These receptors mediate the anabolic and somatogenic effects of IGF-1 and have a higher affinity for IGF-1 compared to insulin (Hill et al., Neurosci., 17:1127-1138 (1986); Lesniak et al., Endocrinol., 123:2089-2099 (1988)). From 3 days after injury greatly increased levels of IGF-1 are produced particularly in the developing CNS (Gluckman et al., Biochem. Biophys. Res. Commun., 182(2);593-599 (1992); Yamaguchi et al., Neurosci. Lett., 128:273-276 (1991)). The effect of IGF-1 as a central neuroprotectant when administered after an insult (Gluckman et al., Biochem. Biophys. Res. Commun., 182(2);593-599 (1992)) (see experiments A and B) suggests a mode of action involving interference with the activated processes leading to cell death. Endogenous and exogenous IGF-1 stimulate peripheral nerve regeneration (Katie et al., Brain Res., 486:396-398 (1989)). IGF-1 has been shown to enhance ornithine decarboxylase activity in normal rat brains (U.S. Pat. No. 5,093,317).
It is an object of the invention to provide a method and/or medicament (therapeutic composition) for treating or preventing CNS damage which will go at least some way to meeting the foregoing desiderata in a simple yet effective manner or which will at least provide the public with a useful choice.